The term compartment syndrome is used in medical practice to characterize a pathological condition characterized by an abnormally increased pressure within a closed volume, a compartment, which is causing reduction or even blockage of the blood and lymph flow through a specified, defined volume. High pressure on the blood vessels impedes the blood flow through veins, capillaries and even arterioles and arteries, alters the working conditions for the interstitial fluid in the extracellular milieu, resulting in depletion of adequate supply of nutrients and oxygen for the cells and tissues within said space. An equally important factor is the lack of drainage of waste products and metabolites, often acidic, which through their accumulation further add to the impairment of the function and metabolism of the cells within said compartment. A net effect of said disturbances is that the pressure in the compartment rises and eventually approaches levels close to the systemic arterial pressure. The actual blood pressure at the entrance of the arterial vascular system to the compartment thus constitutes a key element, determining the maximal level to which the pressure may rise. In avascular structures, such as cartilage and intervertebral discs, adequate supply is dependant on transfer of fluid and other constituents to and from an area by diffusion, by cellular ion and fluid pump systems and by osmotic pressure gradients, requiring proper cell functions. If a strongly elevated CP (compartment pressure) persists, it will cause a severe injury to the involved cells, tissues and organs. Bleedings and swelling of the cells and tissues in said compartment may further add to the damage as do subsequent ischemia. The longer the elapsing time with elevated CP, the more extensive and severe the damage, which eventually turns irreversible and necrotic cell death follows. Mechanical distortion, dislocation and shearing add to the damage. Apoptotic cell death may subsequently add to the initial injury. The CS (compartment syndrome) creates alarming clinical signs such as pain, tenderness, swelling and reduction or even loss of function, and eventually necrosis. The severity of the damage is dependent on the location of the compartment, the types of cells and tissues involved, the characteristics of the extracellular milieu, the actual CP, the metabolic disturbances and its duration to mention some of the key factors of importance for the outcome and long term consequences.
Most compartments in the body are delimited by dense connective tissue, often specialized as sheaths, fasciae, tendons, ligaments, joint capsules or similar noncompliant collagenous membranes, such as the pericardium. Additionally, many endocrine organs, such as the thyroid, and exocrine glands are enclosed by and subdivided by connective tissue membranes and sheaths, therefore forming compartments. Another example of encasing, closed, rigid compartments are bone structures, such as the extremities, skull, vertebrae and facial bones. Each type of cell and tissue exposed to elevated CP is characterized by its own tolerance to prevalent metabolic and mechanical disturbances. However, relief of the CP to normal levels within reasonable time alleviates the damage.
The antisecretory protein is a 41 kDa protein that originally was described to provide protection against diarrhoeal diseases and intestinal inflammation (for a review, see Lange and Lonnroth, 2001). The antisecretory protein has been sequenced and its cDNA cloned. The antisecretory activity seems to be mainly exerted by a peptide located between the positions 35 and 50 on the antisecretory protein sequence. Immunochemical and immunohistochemical investigations have revealed that the antisecretory protein is present in and may also be synthesized by most tissues and organs in a body. Synthetic peptides, comprising the antidiarrhoeic sequence, have been characterized (WO 97/08202; WO 05/030246). Antisecretory factors have previously been disclosed to normalise pathological fluid transport and/or inflammatory reactions, such as in the intestine and the choroid plexus in the central nervous system after challenge with the cholera toxin (WO 97/08202). Addition of antisecretory factors to food and feed was therefore suggested to be useful for the treatment of oedema, diarrhoea, dehydration and inflammation in WO 97/08202. WO 98/21978 discloses the use of products having enzymatic activity for the production of a food that induces the formation of antisecretory proteins. WO 00/038535 further discloses the food products enriched in antisecretory proteins as such.
Antisecretory protein and fragments thereof have also been shown to improve the repair of nervous tissue, and the proliferation, apoptosis, differentiation, and/or migration of stem and progenitor cells and cells derived thereof in the treatment of conditions associated with loss and/or gain of cells (WO 05/030246).
There are at present no drugs available that unequivocally block the rise in pressure and turn it back to normal levels at an established CS or prevent the developing damage at a threatening or ongoing CS. Hypertonic solutions of e.g. urea or mannitol are presently used for selected patients suffering from elevated ICP (intracranial pressure), but the effects are transient lasting for just a few hours, depending on the anatomical location and the actual treatment schedule. Corticosteroids have as well been utilized to counteract elevated ICP, but serious side effects may frequently evolve. Additional drugs have been advocated, but mainly to coop arising symptoms. Lowering the body core temperature in combination with barbiturate anaesthesia is considered beneficial. There is, however, no reliable drug therapy available for CS arising in e.g. muscles, joints and nerves. Surgical intervention constitutes a frequently used treatment, but suffers from the disadvantage of per se adding extra injury and discomfort as well as risks for the development of complications.
A reliable diagnosis of an imminent, developing or established CS may be difficult to make even for an experienced physician. Diagnostic aids based on the use of e.g. ultrasound and magnetic resonance imaging (MRI) have been used, presently often in connection with computerised programs. In the present context, determination of the pressure of the interstitial fluid in the compartment to be investigated was made by measuring the actual pressure with the aid of a very small sensor at the tip of a light guiding glass fibre. The diameter of the probe was 0.4 mm and the diameter of the flexible glass fibre just 0.3 mm, meaning that the injury by the measuring equipment is not likely to be of importance, hardly adding any noticeable effect on the pressure levels. Thereby, the used equipment must be considered to present reliable values on the pressure prevailing in the compartment, both in the extracellular fluid and in certain cases also intracellurlarly in adjacent cells and/or cell aggregates.
Antisecretory factors (AF), specifically proteins and peptides, as described in detail in WO 97/08202, are effective in abolishing hypersecretory conditions and diseases in the intestine, such as diarrhoea. Other examples related to effects of AF in relation to hypersecretory conditions are e.g. inflammatory bowel diseases, brain oedema, glaucoma, elevated intracranial pressure, Morbus Ménière, and mastitis. AF has as well been considered for the treatment of glaucoma (WO 97/08202).